**4. Symptomatic carotid artery stenosis**

When compared to asymptomatic patients the benefit of CEA with recent ipsilateral carotid territory symptoms and moderated to severe carotid stenosis is much greater. In patients who experience a TIA or minor stroke the risk of subsequent stroke or death is very high, especially during the first few days and weeks after an event. [42] Traditionally the mainstay of treatment for symptomatic disease in these patients is surgical intervention with CEA. Recently there has been literature advocating aggressive medical therapy alone may be adequate in certain patients, preventing early stroke after TIA and reducing the need for urgent CEA. The Stroke Prevention Aggressive Reduction of Cholesterol Levels (SPARCL) trail tested whether treatment with atorvastatin reduced strokes in subjects with recent minor stroke or TIA. The study included 4731 participants with a mean follow up of 4.9 years and found that high does Atorvastatin use after TIA or stroke was associated with a 16% relative reduction in risk of fatal or nonfatal stroke. Also patients treated were found to have a 56% reduction in later carotid revascularization compared with placebo. Researchers postulated that the use of statins might help stabilize the arterial wall decreasing events as well as reducing intraoperative complications as well for patients who did proceed with surgery. [43,44] Merwick et al. also evaluated early high dose statin use postulating that pretreatment at TIA onset would modify early stroke risk. They found that non-procedural 7-day stroke risk was 3.8% with statin treatment compared to 13.2% in those not pretreated. [45] Another study by Chimowitz et al. evaluated a different medical treatment looking at recently symptomatic patients with intracranial 79-99% stenosis who were treated with dual antiplatelet therapy versus percuta‐ neous transluminal angioplasty and stenting (PTAS) (gold standard for intracranial lesions). This study found a 30-day rate of stroke or death was found to be 14.7% in the PTAS group and 5.8% in the medical-management group. At one year follow this study concluded that medical management with dual antiplatelet therapy was superior to PTAS and advocates belief this data can be extrapolated to severe, symptomatic extra cranial disease as well. [46,47]. Several other older studies have compared the use of platelet antiaggregants with placebo in treating patients with cerebral ischemia secondary to extra cranial atherosclerosis. [48-51] These results however proved inferior to surgery, which was highlighted in the landmark North American Symptomatic Carotid Endarterectomy Trial.

For asymptomatic patients who continue to have worsening carotid disease even with best medical management the next step in treatment is to consider operative intervention. The current recommendations from the Society for Vascular Surgery is for carotid endarterectomy in asymptomatic patients with carotid stenosis of greater than or equal to 60% as long as the expected combined stroke and mortality rate for the individual surgeon was not greater than 3%. [38] These recommendations are based on three major prospective, randomized trials the Veterans Administration Asymptomatic Carotid Stenosis Study (VA ACS), the Asymptomatic Carotid Atherosclerosis Study (ACAS), and the Asymptomatic Carotid Surgery Trial (ACST). The VA ACS evaluated a total of 444 patients over an 8 year period randomizing them to a surgical group (211) or and a medical group (233). Both groups were treated with aspirin and best medical risk factor control. For the surgical arm, the 30-day mortality rate was 1.9% and the incidence of stroke was 2.4% with a combined stroke and mortality rate of 4.3%. In total, all neurologic events were 30 (14.2%). Conversely, the medical group had a total of 55 (23.6%) neurologic events recorded. These findings were found to be statistically significant with a P value of less than 0.006. [39] However, the study did not find any difference in overall survival rates between groups. This trial gave credence that best medical treatment plus carotid endarterectomy (CEA) would reduce stroke and TIAs versus medical treatment alone in

The ACAS was a NIH-funded randomized trial which included 1662 patients between the ages of 40-79 years with greater than 60% asymptomatic stenosis. Patients were randomized to optimal medical management versus CEA and medical management. The 30-day combined mortality and stroke rate was 2.3%, which accounts for two preoperative deaths and seven preoperative strokes making the actual stroke rate 1.3% and mortality rate 0.1%. After a mean follow up of 2.7 years the overall 5-year risk for ipsilateral stroke, perioperative stroke and death was 5.1% for surgical patients and 11% for the medical group (P=0.004). [40] An absolute risk reduction for stroke and death in the surgical group was calculated to be 53%. [41] One drawback of the ACAS study is that all patients with 60%-99% carotid stenosis were analyzed together and there was no breakdown for event rates by deciles. Nevertheless, their results

Finally a group of European investigators embarked on an additional randomized trial, ACST, to try, in addition to validating CEA for asymptomatic patients with significant stenosis, to identify a higher-risk group of patients. They randomized 3129 patients, both men and women, with greater than 60% asymptomatic unilateral or bilateral carotid artery stenosis to CEA versus best medical therapy. The found a 5 year stroke or death rate to be 6.4% versus 11.8 % (p<0.0001) in the CEA versus medical group, respectively. Overall perioperative stroke or death rate was 3.1%. These results were found to be significant for bother males and females

When compared to asymptomatic patients the benefit of CEA with recent ipsilateral carotid territory symptoms and moderated to severe carotid stenosis is much greater. In patients who

again favored CEA plus medical management over medical management alone.

asymptomatic patients.

6 Carotid Artery Disease - From Bench to Bedside and Beyond

when analyzed separately [18].

**4. Symptomatic carotid artery stenosis**

Two major randomized control trials have reported data to date advocating for CEA in symptomatic patients with 50%-99% stenosis: The North American Symptomatic Carotid EndarterectomyTrial(NASCET)andMedicalResearchCouncilEuropeanCarotidSurgeryTrial (ECST). The NASCET trial was set up to evaluate two subsets of patients those with 70-99% stenosis and those with 30-69% stenosis. In the high-grade stenosis group the 30-day opera‐ tive morbidity and stroke mortality rate for patients was 5%. In the surgical group at 2-year follow-up the incidence of ipsilateral stroke was 9% compared to 26% in the medical treat‐ ment group. This difference represented an absolute risk reduction of 17% in favor of surgical management and a relative risk reduction of 71% at the end of the 18-month follow up. Mortali‐ ty rates were also measured at the end of 18 months yielding 12% mortality rate in the medi‐ cal group compared to a significantly lowerrate of 5% in the surgical group. [52,53]. The results for the moderate stenosis group were also reported. The 30-day combined mortality, disa‐ bling stroke rate, and non-disabling stroke rate was 6.7%. At 5 year follow up in this group the ipsilateral stroke rate was 22.2% in the medical patients and 16.7% in the surgical patients. [54]

The ECST trial was a European randomized control trial that enrolled patients over 10 years almost concurrently with the NASCET trial. There were 2518 patients with nondisabling ischemic stroke, TIA or retinal infarct due to a stenotic lesion in the ipsilateral carotid artery randomized to either medical management with aspirin or surgery. At 3 years, the risk of stroke was found to be 26.5% in the medical group compared to 7% in the surgery group with an absolute reduction of 14.9%. The actual incidence of ipsilateral stroke was 2.8% in the surgery group versus 16.8% in the medical group. [55] ECST trial also evaluated gender, age, severity of stenosis, plaque morphology, and time since last event. They found that risk of events increased with age and with male gender. They did not find any benefit for surgery over medical treatment in the mild stenosis group (10%-29%) unlike the severe stenosis group, which showed a 6-fold reduction in subsequent strokes over 3 years. [56]

5.4% for CAS and 10.2% for CEA. [61] Their results found that CAS with cerebral protection was not inferior to CEA. This study, however had several limitations including failure to randomize >50% of patients, unaccounted for elevated incidence of perioperative stroke, and possible reporting bias. The Carotid Revascularization Endarterectomy versus Stent Trial (CREST) enrolled more than 1000 asymptomatic patients. Stroke and death rates after CAS were 2.6% and 1.1% respectively with a difference between CAS and CEA in asymptomatic patients for any periprocedural stroke being 2.5% versus 1.4%. [62-64] These results did not show significant difference between CAS and CEA. The results from this study, however, were based on procedures performed by highly experienced operators and have not been replicated

Evaluation and Treatment of Carotid Artery Stenosis

http://dx.doi.org/10.5772/57258

9

(b)

(c) (d)

**Figure 3.** 70 year old Male with a history of squamous cell carcinoma status post neck radiation and hemiglossectomy found to have a 90% asymptomatic left common carotid artery stenosis. A: Angiogram of left common carotid artery stenosis (arrow) B. Angiogrom showing cerebral protection device located in the left internal carotid artery (dashed arrow) and stent placed in common carotid artery stenosis (black arrow). C. Post stent placement angioplasty balloon

inflated (arrow) D. Completion angiogram showing minimal residual stenosis after stent placed.

(a)

by other trials. [65]

Based on these randomized studies there seems to be a consensus on which patients would benefit from operative intervention after an ischemic event, however the timing of interven‐ tion has been much debated. The risk ofrecurrent stroke after TIA or minor stroke is the highest within the first 7-10 days. According to a meta-analysis by Giles et al the risk of stroke after TIA is 6.7% at 48 hours and 10% at 7 days with more than half of the strokes occurring within the first 7 days doing so within the first 24 hours after the inciting event. [57,58] In another study by Ois et al. the rate of recurrent stroke in symptomatic patients with greater then 50% stenosis was determined to be 20.9% in the first 72 hours, 6.7% between 72 hours and 7 days and 3.7% between7 and14days.[59]These results support early interventioninthe first 48hours because the risk of recurrent stroke appears to outweigh the operative risk in patients who are medical‐ ly stable and have relatively small or no infarcts on imaging studies. Alternatively, for a completed stroke researchers advocate delayed surgical intervention for at least 4-6 weeks due to the risk of converting an ischemic cerebral infarction into a hemorrhagic one. Giordano et al reported on 49 CEAs done after a completed acute stroke. 27 of these were performed within 5 weeks of the event and 22 were done between 5 and 20 weeks. The early intervention group had a morbidity and mortality of 18.5% compared to nothing for the later group. [60] These results seem to corroborate with observations in both the NASCET and ECST trials.
